Nonsteroidal anti-inflammatory drugs (NSAIDs), which are drugs that reduce pain and inflammation, are widely used for alleviating symptoms such as headaches, osteoarthritis, rheumatoid arthritis, low back pain and musculoskeletal disease. Furthermore, these drugs have been reported to have the effects of ameliorating neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease, as well as suppressing brain damage caused by inflammatory reactions by blocking neuroinflammatory pathways.
Most nonsteroidal anti-inflammatory drugs act by inhibiting cyclooxygenase (COX), which is involved in the biosynthesis of prostaglandin. Cyclooxygenase includes two kinds of enzymes, namely cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), in which COX-1 is involved in the synthesis of prostaglandin, which is normally produced to maintain the biological function in the human body. Specifically, COX-1 plays a role in synthesizing prostaglandin to maintain the function of each organ in the gastrointestinal tract, kidneys, and platelets, and is present in vascular endothelial cells, gastric mucosa and the kidneys and has a gastric mucosal protective action or a homeostatic function to regulate renal blood flow. Additionally, COX-2 is expressed by inflammatory cells during inflammation and synthesizes prostaglandin, which causes inflammation, to thus induce inflammation at the inflamed site and maintain inflammation.
Examples of isotypes derived from prostaglandin include thromboxane (TXA2), showing platelet aggregation action, and prostacyclin (PGI2), showing platelet aggregation inhibitory action. Thromboxane is produced by COX-1 and prostacyclin is produced by COX-2. Typical nonsteroidal anti-inflammatory drugs are non-selective inhibitors that inhibit both COX-1 and COX-2, and may cause not only anti-inflammatory effects due to COX-2 inhibition but also gastrointestinal side effects such as gastritis, gastric ulcers, perforation, and gastrointestinal bleeding due to COX-1 inhibition. On the other hand, COX-2 selective inhibitors that selectively inhibit COX-2 reduce gastrointestinal side effects caused by inhibition of COX-1, but selectively inhibit prostacyclin without inhibiting thromboxane, thereby causing platelet aggregation, undesirably resulting in cardiovascular side effects.
Ibuprofen is a propionic acid derivative and is the most commonly used non-aspirin non-steroidal anti-inflammatory agent that may be purchased in most countries without a prescription. Long-term use of ibuprofen may delay Alzheimer's disease and reduce the risk of developing Parkinson's disease. A study found that people who took ibuprofen on a regular basis had 38% less risk of developing Parkinson's disease than those taking other non-steroidal anti-inflammatory drugs.
However, such nonsteroidal anti-inflammatory drugs have limited ability to penetrate the brain due to the blood-brain barrier. The blood-brain barrier present in the cerebral blood vessels is a barrier separating the cerebrospinal fluid from the blood, and has high selective permeability and thus functions to protect the brain from harmful substances. However, this blood-brain barrier has hampered the development of brain-related therapies by blocking the passage of drugs for treating brain disease such as tumors, Alzheimer's disease, and Parkinson's disease, as well as harmful substances. Meanwhile, ibuprofen is ionized into anions at a physiological pH and binds to plasma proteins extensively, thus staying in the body for a long time and circulating in the body, resulting in the drug being distributed throughout an increased volume. Thereby, only a small amount of ibuprofen reaches the brain, and thus a large dose thereof is required to increase the efficacy of the drug. Moreover, long-term use of ibuprofen may also cause side effects such as cardiovascular and gastrointestinal disorders. Therefore, it is necessary to develop ibuprofen that is effective at preventing and alleviating neurodegenerative disease through penetration into the brain through the blood-brain barrier even when used in a small dose.